Twenty-five percent of adult woment with natural rubella infection or immunization with attenuated rubella vaccine develop transient or chronic arthritis. To understand the mechanisms of RV -associated disease, we are analyzing the function of both the essential elements of virus RNA and their interaction with host and viral components during viral replication. We have identified two host-encoded proteins (La and calreticulin),that are known autoantigens and are essential for RV replication. The involvement of autoantigens in RV pathogenesis is of clinical interest, because antibodies to autoantigensoccur commonly in autoimmune diseases. We found that sera from patients with Sjorgens syndrome and Systemic Lupus Erythrematous have antibodies against RV-autoantigen complexes and that there was a significant anti-La response in RV infected people 2 years post-infection. The antibody response to RV-autoantigen complexes in infected patients suggests that an autoimmune response may occur in RV-associated arthropathy. The project deals directly with the safety issues of live-viral vaccines in general and of RV vaccine in particular. Research conducted with RV will serve as a guideline for understanding vaccine related adverse reactions such as RV vaccine-associated acute or chronic arthritis. It also provides insight in the design of future viral vaccines free of adverse effects. Further, we have developed in-house know-how of modern techniques used in development of recombinant viral vaccines currently being developed by the companies, thus enabling the FDA to provide guidance to the manufacturers in such issues. Our RV research has also an added impact on the development of new assays and methodologies useful in evaluating the purity of biologics during manufacturing process and lot release testing. Knowledge gained from the research done with RV can provide impetus in the development of regulatory policy to evaluate manufacturing process for live-viral vaccines as well as recombinant vaccines that are more efficient and less cumbersome.